Combination of cytoplasmic and nuclear patterns on Hep-2 antinuclear antibody is useful as a screening test for anti-synthetase syndrome.

OBJECTIVE: This study aimed to establish a screening model for differentiating anti-synthetase syndrome (ASS) from other ANA-associated rheumatic diseases (AARDs) using a combination of cytoplasmic and non-cytoplasmic ANA (ncANA) patterns. METHODS: : This retrospective observational study included patients with AARDs such as SLE, SSc, SS, MCTD and PM/DM who underwent ANA screening between April 2012 and December 2021. Variables included age, sex, ANA patterns (Cytoplasmic and ncANA) and titres. Logistic regression analysis of Cytoplasmic and ncANA patterns was performed to differentiate ASS from other AARDs. RESULT: : The 981 diagnosed cases of AARDs consisted of SS (n = 451), SSc (n = 264), SLE (n = 201), PM/DM (n = 104), MCTD (n = 52) and ASS, including PM/DM (n = 64). Of these, 155 patients had ≥2 overlapping diseases; however, there was no overlap between AARDs and ASS. ASS is more likely to occur when the cytoplasmic titre is positive and the ncANA <320. Receiver operating characteristic analysis of the Cytoplasmic and ncANA range revealed an area under the receiver operating characteristic curve of 0.885 (95% CI: 0.844-0.927). CONCLUSION: : It is important to detect cytoplasmic patterns as an ANA screening test for ASS diagnosis, even if the titre is low. Additionally, combining the cytoplasmic and ncANA patterns yields more accurate ASS screening results.

Management and outcomes of interstitial lung disease associated with anti-synthetase syndrome: A systematic literature review.

BACKGROUND: Anti-synthetase syndrome (ASS) is a chronic autoimmune condition, with interstitial lung disease (ILD) being a key feature. This systematic literature review (SLR; CRD42023416414) aimed to summarise treatments and outcomes of ILD associated with ASS (ASS-ILD). METHODS: Databases were searched for articles discussing ASS-ILD management and outcomes, published 1946-September 2023.Screening and data-extraction were performed by two reviewers. Meta-analysis, using a random effects model, and paired t-tests, were undertaken where appropriate to evaluate post-treatment-change in Pulmonary Function Tests (PFT). RESULTS: Ten articles were included, comprising 514 patients: 67.8% female, mean age 52.4years (SD4.6). Baseline high-resolution computed tomography was documented in 447 patients (86.9%); the most common pattern was non-specific interstitial pneumonia (n = 220; 49.2%). The most common myositis-associated autoantibody was anti-Jo1 (48%) with 27.8% having associated anti-Ro52 antibodies.Pooled estimates, after meta-analysis, for baseline Forced Vital Capacity (FVC) was 60.8% predicted (SE 2.1), and Diffusion Capacity of Lungs for Carbon Monoxide (DLco) was 49.8% (SE 3.5). After one-year, pooled improvement in FVC was 14.1% from baseline (SE 3.1) and in DLco was 15.1% (SE 2.8). Paired t-test demonstrated significant overall improvement in FVC (p = 0.007) and DLco (p = 0.002).Patients receiving RTX had 12.2% improvement in FVC and 2.9% increase in DLco at one-year; for patients receiving CYC, there was 17% improvement and 6.3% increase, respectively. 28 deaths were reported. CONCLUSION: Our SLR, the first to summarise management and outcomes of ASS-ILD, found no conclusive difference between effectiveness of treatments. More robust trials are required to reduce morbidity and mortality resulting from ASS-ILD.

Anti-synthetase and myelodysplastic syndromes with deep morphea: an example of shared immunopathogenesis? A case-based review.

Anti-synthetase syndrome (AS) is a subset of idiopathic inflammatory myopathy (IIM) characterized by the presence of anti-aminoacyl-transfer RNA synthetase accompanied by myositis, interstitial lung disease and other clinical features. According to a recent multicentric study, 31% of AS patients present skin lesions compatible with dermatomyositis, but sclerodermiform features are rare. Therefore, we aimed to report the case of a patient with simultaneous diagnosis of AS, deep morphea, vasculitic neuropathy, and myelodysplastic syndrome and review the current literature regarding these uncommon associations. A 57 year old man with axial and symmetrical proximal muscle weakness, skin thickening and B symptoms, later diagnosed with PL7 + AS, deep morphea, myelodysplastic syndrome (MDS) and vasculitic neuropathy documented by histopathologic studies and immunologic assessments. Since both AS and deep morphea share the vasculopathic changes and type II interferon-induced inflammation, we hypothesize that they may share pathogenic mechanisms. The muscle biopsy of the patient was consistent with AS and showed focal neutrophil infiltration. The patient received intensive immunosuppressive therapy for AS and vasculitic neuropathy, with high dose steroids, intravenous immunoglobulin (IVIg) and rituximab. Nonetheless, he suffered an unfavorable evolution with a fatal outcome due to septic shock. Albeit sclerodermiform features are rare in patients with AS, we propose a pathogenic link among AS, deep morphea and the autoimmune/autoinflammatory signs of MDS. The vasculopathic changes along with the activation of the innate and adaptive immune system leading to the production of proinflammatory cytokines may have been one of the contributing factors for the coexisting diagnosis of the patient.

Heterogeneity in nomenclature and abbreviation usage for anti-synthetase syndrome: a scoping review.

Anti-synthetase syndrome constitutes a dynamically evolving subset of Idiopathic Inflammatory Myopathy, however, the nomenclature and abbreviations for this syndrome are plagued by heterogeneity, leading to lack of consistency in literature. The objective of this study is to evaluate existing diversity in disease names and abbreviations, with a future goal to develop consensus on the nomenclature. A scoping review format was used for analysis. A comprehensive PUBMED search was conducted from January 1, 1984 (the initial description of anti-synthetase autoantibodies) to November 30, 2023, encompassing all pertinent articles published within this timeframe. Search terms included, ((antisynthetase syndrome) OR (anti synthetase syndrome)) OR (anti-synthetase syndrome)). The articles were screened for presence of terminology and abbreviations used. The search yielded 936 items with the specified terms. After excluding 303 irrelevant articles and 58 non-English publications, the remaining n = 575 articles underwent detailed review of the abstract and full article. Out of n = 575, 54.7% (n = 314) used 'antisynthetase syndrome' and 43.4% (n = 249) preferred 'anti-synthetase syndrome' with few novel names also. Among these, 394 articles used abbreviations while 181 did not. Most utilized term was ASS; in 64.7% (n = 255), followed AS in 11.9% (n = 47), ASSD in 9.9% (n = 39) and ASyS in 7.6% (n = 30). A discordance in nomenclature is evident, with about half using antisynthetase syndrome and other half using anti-synthetase syndrome. Moreover, significant heterogeneity exists in abbreviation use aswell. There is a pressing need to bridge this disparity and establish a uniform identifier for the disease with an objective to develop greater coherence in future research, educational initiatives, and interdisciplinary collaboration.

Anti-synthetase syndrome in a child with pneumomediastinum: a case report and literature review.

BACKGROUND: Anti-synthetase syndrome (ASS) is a group of rare clinical subtypes within inflammatory myopathies, predominantly affecting adult females. Instances of critical illness associated with ASS in children are even rarer. CASE PRESENTATION: We report the case of a 7-year-old boy finally diagnosed with ASS, combined with pneumomediastinum. He presented with intermittent fever persisting for 12 days, paroxysmal cough for 11 days, chest pain, and shortness of breath for 4 days, prompting admission to our hospital. Pre-admission chest CT revealed diffuse pneumomediastinum, subcutaneous pneumatosis in the neck and bilateral chest wall, consolidation, atelectasis, and reticular nodular shadowing in both lungs, as well as pericardial effusion and bilateral pleural effusions. Laboratory tests revealed a positive result for serum MP immunoglobulin M (MP-IgM) and MP immunoglobulin G (MP-IgG). The patient was initially diagnosed with mycoplasma pneumoniae (MP) infection, and following 3 days of antibiotic treatment, the patient's tachypnea worsened. Positive results in muscle enzyme antibody tests included anti-PL-12 antibody IgG, anti-Jo-1 antibody IgG, and anti-RO-52 antibody IgG. Ultrasonography detected moderate effusions in the right shoulder, bilateral elbow, and knee joints. Corticosteroids pulse therapy was initiated on the 27th day following disease onset, and continued for 3 days, followed by sequential therapy for an additional 12 days. The child was discharged on the 43rd day, and subsequent follow-up revealed a significant improvement in consolidation and interstitial lesions in both lungs. CONCLUSIONS: ASS in children may combine with rapidly progressive interstitial lung disease (RPILD) and pneumomediastinum. It is crucial to promptly identify concurrent immunologic abnormalities during the outbreak of MP, particularly when the disease exhibits rapid progression with ineffective conventional antibiotic therapy.

Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies.

OBJECTIVES: Autoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to known myositis-specific autoantibodies. We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM. METHODS: Plasma samples from 217 patients with IIM according to 2017 EULAR/ACR criteria, including 50 patients with ASSD, 165 without, and two with unknown ASSD status were identified retrospectively, as well as age and gender-matched sera from 156 population controls, and 219 disease controls. Patients with previously documented ASSD had to test positive for at least one of the five most common anti-aaRS autoantibodies (anti-Jo1, -PL7, -PL12, -EJ, and -OJ) and present with one or more of the following clinical manifestations: interstitial lung disease, myositis, arthritis, Raynaud's phenomenon, fever, or mechanic's hands. Demographics, laboratory, and clinical data of the IIM cohort (ASSD and non-ASSD) were compared. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 117 recombinant protein variants, representing 33 myositis-related proteins, including all nineteen cytoplasmic aaRS. Prospectively collected clinical data for the IIM cohort were retrieved and compared between groups within the IIM cohort and correlated with the results of the autoantibody screening. Principal component analysis was used to analyze clinical manifestations between ASSD, non-ASSD groups, and individuals with novel anti-aaRS autoantibodies. RESULTS: We identified reactivity towards 16 aaRS in 72 of the 217 IIM patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four previously seronegative patients for myositis-specific autoantibodies and eight with previously detected myositis-specific autoantibodies. IIM individuals with novel anti-aaRS autoantibodies (n = 12) all had signs of myositis, and they had either muscle weakness and/or muscle enzyme elevation, 2/12 had mechanic's hands, 3/12 had interstitial lung disease, and 2/12 had arthritis. The individuals with novel anti-aaRS and a pathological muscle biopsy all presented widespread up-regulation of major histocompatibility complex class I. The reactivities against novel aaRS could be confirmed in ELISA and western blot. Using the multiplex bead array assay, we could confirm previously known reactivities to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n = 45)) and identified patients positive for anti-Zo, -KS, and -HA (n = 10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was also detected in controls. CONCLUSION: Our results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance.

Myocarditis in anti-synthetase syndrome: clinical features and diagnostic modalities.

OBJECTIVES: Myocarditis is an overlooked manifestation of anti-synthetase syndrome (ASS). Our study describes the clinical and instrumental features of ASS-myocarditis and evaluates the diagnostic performance of cardiac magnetic resonance (CMR) with mapping techniques. METHODS: Data from ASS-patients were retrospectively analyzed. CMR data of patients diagnosed with myocarditis, including late gadolinium enhancement (LGE), T2-ratio, T1-mapping, extra-cellular volume (ECV) and T2-mapping, were reviewed. Myocarditis was defined by the presence of symptoms of heart involvement with increased high-sensitive troponin T (hs-TnT) and/or NT-proBNP and at least an instrumental abnormality. Clinical features of ASS patients with and without myocarditis were compared. A p value<0.05 was considered. RESULTS: Among a cohort of 43 ASS-patients (median age 58[48.0-66.0] years; females 74.4%; anti-Jo1 53.5%), 13(30%) were diagnosed with myocarditis. In 54% of patients, myocarditis was diagnosed at clinical onset. All ASS-myocarditis patients had at least one CMR abnormality: increased ECV in all cases, presence of LGE, increased T1 and T2-mapping in 91%. The 2009-Lake Louis criteria (LLC) were satisfied by 6 patients, the 2018-LLC by 10. With the updated LLC, the sensitivity for myocarditis improved from 54.6% to 91.0%. ASS-patients with myocarditis were more frequently males(53% vs 13%;p=0.009) with fever(69% vs 17%;p=0.001), and had higher hs-TnT (88.0[23.55-311.5] vs 9.80[5.0-23.0]ng/L; p < 0.001), NT-proBNP(525.5[243.5-1575.25] vs 59.0[32.0-165.5;p=0.013]pg/ml;p=0.013) and C-reactive protein(CRP)(7.0[1.7-15.75] vs 1.85[0.5-2.86]mg/L;p=0.011) compared to those without myocarditis. CONCLUSION: In ASS, myocarditis is frequent, even at clinical onset. ASS-patients with myocarditis frequently presented with fever and increased CRP, suggesting the existence of an inflammatory phenotype. The use of novel CMR mapping techniques may increase the diagnostic sensitivity for myocarditis in ASS.

Clinical heterogeneity and prognostic factors of anti-synthetase syndrome: a multi-centered retrospective cohort study.

OBJECTIVE: Anti-synthetase syndrome (ASyS) patients have heterogeneous clinical manifestations with different initial presentations, complications, and outcomes. This study aimed to assess the clinical characteristics and complications in patients with ASyS, and to identify factors that were associated with the survival of ASyS patients. METHODS: This was a retrospective multicentre longitudinal study. Patients fulfilling either the Connor's criteria or Solomon's criteria for ASyS were recruited. Electronic health records were reviewed until October 2022. Multivariate Cox-regression analysis was used to determine the independent prognostic factors. Auto-antibodies were checked by commercial immunoassays. RESULTS: A total of 205 patients (anti-Jo-1 49.3%, anti-PL-7 19.0%, anti-EJ 11.2%, anti-PL-12 10.2% and anti-OJ 3.4%) were included. The median follow-up time was 4 years. The time from symptoms onset to diagnosis was significantly longer for non-anti-Jo1 patients (median 5 vs 3 months). Common initial presentations included myositis (56.1%), arthritis (54.6%), and interstitial lung disease (ILD) (54.1%). Patients with anti-Jo-1 had significantly higher muscle enzyme levels and more arthritis. All patients with anti-EJ would develop ILD on follow-up and malignancy was noted in 28.6% of the anti-OJ positive patients. 15.6% of the patients died and pulmonary diseases (ILD or pneumonia) were the major causes. Age at diagnosis, malignancy and rapidly progressive-ILD were independently associated with mortality, while joint manifestation was a protective factor. CONCLUSION: In view of the heterogeneity of clinical presentation of ASyS, high index of suspicion and early checking of specific autoantibodies might help prompt diagnosis of ASyS and detection of related complications.

Intravenous Immunoglobulin in Idiopathic Inflammatory Myopathies: a Practical Guide for Clinical Use.

PURPOSE OF REVIEW: Idiopathic inflammatory myopathies (IIM) are a complex family of autoimmune systemic disorders which often affect muscle and/or skin. IIM cause significant morbidity and mortality, but optimal treatment is uncertain. This review provides a practical guide for using intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) in the management of IIM, including dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myositis (IMNM), and spontaneous inclusion body myositis (IBM), based on relevant recent literature and experience. We summarize pertinent considerations when using IVIG in special circumstances, including myositis-related dysphagia, interstitial lung disease (ILD), calcinosis cutis, and pregnant patients. This review also discusses IVIG safety, available formulations, and costs. RECENT FINDINGS: While IVIG has been used de facto for severe IIM for over 30 years, prior clinical trials of IVIG were notably limited. Recently, however, IVIG has proven safe and effective against IIM in several high-impact publications, including a large prospective, randomized placebo-controlled phase III study in DM. IVIG is useful against both muscular and extra-muscular manifestations in many types of IIM. It can be used as a first-line, steroid-sparring agent or as add-on to other treatments, tailored to specific clinical IIM scenarios. It is generally well-tolerated and has good safety profile, but accessibility and cost still limit its use.

Therapeutic plasma exchange for steroid refractory idiopathic inflammatory myopathies with interstitial lung disease.

BACKGROUND: Idiopathic inflammatory myopathies (IIMs) encompass many rheumatologic diseases characterized by inflammatory muscle disease, typically unified by proximal muscle weakness. A subset of patients with IIM present with interstitial lung disease (ILD) with identifiable antibodies such as in anti-synthetase syndrome (AS) with antibodies to aminoacyl-tRNA synthetases, and clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated protein 5 (MDA5). Recent case reports demonstrate response to therapeutic plasma exchange (TPE) or column filtration plasmapheresis in IIM with ILD resistant to medical management. We present our experience with eight patients with IIM with ILD undergoing TPE at a large US-based hospital system. PATIENT CHARACTERISTICS: Eight patients with IIM with ILD were treated with TPE over the last 10 years. The therapy consisted of 5-7 one plasma volume exchanges every other day to daily. Seven of eight patients had identifiable antibodies. RESULTS: Following completion of TPE, seven of eight demonstrated improvement in pulmonary function despite lack of improvement of pulmonary function with standard therapy. CONCLUSION: In antibody-mediated, treatment refractory IIM with ILD, TPE may be a viable intervention. This is a disease for which the role of apheresis is evolving. CLINICAL TRIAL REGISTRATION: Not application.

Anti-synthetase syndrome-associated interstitial lung disease possibly caused by atezolizumab in a patient with lung adenocarcinoma: a case report.

BACKGROUND: Anti-aminoacyl-tRNA synthetase (ARS) antibody-positive patients present with a variety of symptoms, including interstitial lung disease (ILD), which is termed anti-synthetase syndrome (ASS). But it is rare that ASS-ILD is considered an immune-related adverse event after the use of immune checkpoint inhibitors (ICIs). CASE PRESENTATION: A 47-year-old male with advanced lung adenocarcinoma was treated with platinum and ICI combination immunotherapy and was followed up as an outpatient. Nine months after the start of treatment, he developed a fever and cough, and imaging findings showed lung consolidations in the bilateral lower lung fields. The patient was positive for anti- ARS antibodies and was considered to have developed ASS-ILD due to ICIs remitted with steroid therapy. The patient was found to be positive for anti-ARS antibodies before ICI administration, and the antibody titer was elevated compared to that before ICI administration. CONCLUSIONS: The examination of anti-ARS antibodies pior to the administration of ICIs may be useful in predicting the development of ASS-ILD.

[Significance of anti-Jo-1 antibody's clinical stratification in idiopathic inflammatory myopathy and disease spectrum].

OBJECTIVE: To investigate the significance of anti-histidyl tRNA synthetase (Jo-1) antibody in idiopathic inflammatory myopathies (IIM) and its diseases spectrum. METHODS: We enrolled all the patients who were tested positive for anti-Jo-1 antibody by immunoblotting in Peking University People's Hospital between 2016 and 2022. And the patients diagnosed with anti-synthetase antibody syndrome (ASS) with negative serum anti-Jo-1 antibody were enrolled as controls. We analyzed the basic information, clinical characteristics, and various inflammatory and immunological indicators of the patients at the onset of illness. RESULTS: A total of 165 patients with positive anti-Jo-1 antibody were enrolled in this study. Among them, 80.5% were diagnosed with connective tissue disease. And 57.6% (95/165) were diagnosed with IIM, including ASS (84/165, 50.9%), immune-mediated necrotizing myopathy (7/165, 4.2%) and dermatomyositis (4/165, 2.4%). There were 23.0% (38/165) diagnosed with other connective tissue disease, mainly including rheumatoid arthritis (11/165, 6.7%), undifferentiated connective tissue disease (5/165, 3.0%), interstitial pneumonia with autoimmune features (5/165, 3.0%), undifferentiated arthritis (4/165, 2.4%), Sjögren's syndrome (3/165, 1.8%), systemic lupus erythematosus (3/165, 1.8%), systemic vasculitis (3/165, 1.8%), and so on. Other cases included 3 (1.8%) malignant tumor patients, 4 (2.4%) infectious cases and so on. The diagnoses were not clear in 9.1% (15 /165) of the cohort. In the analysis of ASS subgroups, the group with positive serum anti-Jo-1 antibody had a younger age of onset than those with negative serum anti-Jo-1 antibody (49.9 years vs. 55.0 years, P=0.026). Clinical manifestations of arthritis (60.7% vs. 33.3%, P=0.002) and myalgia (47.1% vs. 22.2%, P=0.004) were more common in the ASS patients with positive anti-Jo-1 antibody. With the increase of anti-Jo-1 antibody titer, the incidence of the manifestations of arthritis, mechanic hands, Gottron sign and Raynaud phenomenon increased, and the proportion of abnormal creatine kinase and α-hydroxybutyric dehydrogenase index increased in the ASS patients. The incidence of myalgia and myasthenia were significantly more common in this cohort when anti-Jo-1 antibody-positive ASS patients were positive for one and more myositis specific antibodies/myositis associated autoantibodies (P < 0.05). CONCLUSION: The disease spectrum in patients with positive serum anti-Jo-1 antibody includes a variety of diseases, mainly ASS. And anti-Jo-1 antibody can also be found in many connective tissue diseases, malignant tumor, infection and so on.

Significance of Sjögren's syndrome and anti-cN1A antibody in myositis patients.

OBJECTIVE: We recently recorded a high prevalence of inclusion body myositis (IBM) in patients with Sjögren's syndrome (SS). Whether myositis patients with SS differ from myositis patients without SS in terms of the characteristics of the myositis is currently unknown. Anti-cytosolic 5'-nucleotidase 1 A (cN1A) has recently been proposed as a biomarker for IBM but is also frequent in SS. Whether anti-cN1A is independently associated with IBM is still an open question. We aimed to assess the significance of SS and anti-cN1A in myositis patients. METHODS: Cumulative data on all myositis patients (EULAR/ACR 2017 criteria) screened for SS (ACR/EULAR 2016 criteria) in a single centre were analysed. Ninety-nine patients were included, covering the whole spectrum of EULAR/ACR 2017 myositis subgroups and with a median follow-up of 6 years (range 1.0-37.5). The 34 myositis patients with SS (myositis/SS+) were compared with the 65 myositis patients without SS (myositis/SS-). RESULTS: . IBM was present in 24% of the myositis/SS+ patients vs 6% of the myositis/SS- group (P = 0.020). None of the IBM patients responded to treatment, whether they had SS or not. Anti-cN1A was more frequent in myositis/SS+ patients (38% vs 6%, P = 0.0005), independently of the higher prevalence of IBM in this group (multivariate P value: 0.02). Anti-cN1A antibody specificity for IBM was 0.96 (95% CI: 0.87, 0.99) in the myositis/SS- group but dropped to 0.70 (95% CI: 0.48, 0.85) in the myositis/SS+ group. INTERPRETATION: In myositis patients, SS is associated with IBM and with anti-cN1A antibodies, independently of the IBM diagnosis. As a consequence, anti-cN1A has limited specificity for IBM in myositis patients with SS.

Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.

Anti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established.To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12+ patients compared to Jo-1+ patients, while PL-7+ patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138+ plasma cells and CXCL12+/CXCL13+CD20+ B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase+ activated mesenchymal fibroblasts and CD68+MHC-II+CD169+ macrophages. An MHC-I+ and MHC-II+ MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis.

Idiopathic inflammatory myopathies: CT characteristics of interstitial lung disease and their association(s) with myositis-specific autoantibodies.

OBJECTIVES: Interstitial lung disease (ILD), one of the most common extramuscular manifestations of idiopathic inflammatory myopathies (IIMs), carries a poor prognosis. Myositis-specific autoantibody (MSA)-positivity is a key finding for IIM diagnosis. We aimed to identify IIM-associated lung patterns, evaluate potential CT-ILD finding-MSA relationships, and assess intra- and interobserver reproducibility in a large IIM population. METHODS: All consecutive IIM patients (2003-2019) were included. Two chest radiologists retrospectively assessed all chest CT scans. Multiple correspondence and hierarchical cluster analyses of CT findings identified and characterized ILD-patient subgroups. Classification and regression-tree analyses highlighted CT-scan variables predicting three patterns. Three independent radiologists read CT scans twice to assign patients according to CT-ILD-pattern clusters. RESULTS: Among 257 IIM patients, 94 (36.6%) had ILDs; 87 (93%) of them were MSA-positive. ILD-IIM distribution was 54 (57%) ASyS, 21 (22%) DM, 15 (16%) IMNM, and 4 (4%) IBM. Cluster analysis identified three ILD-patient subgroups. Consolidation characterized cluster 1, with significantly (p < 0.05) more frequent anti-MDA5-autoantibody-positivity. Significantly more cluster-2 patients had a reticular pattern, without cysts and with few consolidations. All cluster-3 patients had cysts and anti-PL12 autoantibodies. Clusters 2 and 3 included significantly more ASyS patients. Intraobserver concordances to classify patients into those three clusters were good-to-excellent (Cohen κ 0.64-0.81), with good interobserver reliability (Fleiss's κ 0.56). CONCLUSION: Despite the observed IIM heterogeneity, CT-scan criteria enabled ILD assignment to the three clusters, which were associated with MSAs. Radiologist identification of those clusters could facilitate diagnostic screening and therapeutics. Interstitial lung disease in patients with idiopathic inflammatory myopathy could be classified into three clusters according to CT-scan criteria, and these clusters were significantly associated with myositis-specific autoantibodies. KEY POINTS: • Cluster analysis discerned three homogeneous groups of interstitial lung disease (ILD) for which cysts, consolidations, and reticular pattern were discriminatory, and associated with myositis-specific autoantibodies. • Like muscle- and extramuscular-specific phenotypes, myositis-specific autoantibodies are also associated with specific ILD patterns in patients with idiopathic inflammatory myopathies.

Generation and validation of recombinant antibodies to study human aminoacyl-tRNA synthetases.

Aminoacyl-tRNA synthetases (aaRSs) have long been viewed as mere housekeeping proteins and have therefore often been overlooked in drug discovery. However, recent findings have revealed that many aaRSs have noncanonical functions, and several of the aaRSs have been linked to autoimmune diseases, cancer, and neurological disorders. Deciphering these roles has been challenging because of a lack of tools to enable their study. To help solve this problem, we have generated recombinant high-affinity antibodies for a collection of thirteen cytoplasmic and one mitochondrial aaRSs. Selected domains of these proteins were produced recombinantly in Escherichia coli and used as antigens in phage display selections using a synthetic human single-chain fragment variable library. All targets yielded large sets of antibody candidates that were validated through a panel of binding assays against the purified antigen. Furthermore, the top-performing binders were tested in immunoprecipitation followed by MS for their ability to capture the endogenous protein from mammalian cell lysates. For antibodies targeting individual members of the multi-tRNA synthetase complex, we were able to detect all members of the complex, co-immunoprecipitating with the target, in several cell types. The functionality of a subset of binders for each target was also confirmed using immunofluorescence. The sequences of these proteins have been deposited in publicly available databases and repositories. We anticipate that this open source resource, in the form of high-quality recombinant proteins and antibodies, will accelerate and empower future research of the role of aaRSs in health and disease.

Long-term efficacy of adding intravenous immunoglobulins as treatment of refractory dysphagia related to myositis: a retrospective analysis.

OBJECTIVE: Dysphagia is a life-threating manifestation of idiopathic inflammatory myopathies (IIM). However, we lack a univocal protocol for its treatment. The aim of this retrospective analysis was to evaluate the effectiveness of a step-up strategy by adding a 1-day pulse of IVIGs to immunosuppressants in IIM patients with refractory dysphagia diagnosed by Eating Assessment Tool (EAT)-10 and fibreoptic endoscopic evaluation of swallowing (FEES). METHODS: Dysphagia was defined as a pharyngo-oesophageal disturbance associated with EAT-10 score ≥3 and at least one FEES abnormality among propulsion failure, solid or liquid stasis. Eighteen out of 154 IIM patients had FEES-confirmed dysphagia and underwent 1 day IVIG 2 g/kg repeated 1 month apart for 3 months, because of dysphagia refractory to high-dose glucocorticoids with methotrexate and/or azathioprine. Clinical characteristics along with myositis-specific antibodies and muscle histopathological findings were studied in FEES-dysphagia IIM and IIM control patients. RESULTS: After three monthly doses of IVIG, EAT-10 score dropped with complete recover of defective propulsion and progressive decrease in percentage of both solid and liquid stasis. At 52-weeks' follow-up, reached in 12 patients, all these parameters were stable or further improved. An improvement in manual muscle strength test and a steroid-sparing effect of IVIG were also observed. Anti-PM/Scl 75/100 antibodies were much more frequent in the FEES-dysphagia group, while anti-Jo1 antibody was rarely detected. CONCLUSION: Our treatment schedule with 2 g/kg IVIG was effective for IIM-associated refractory dysphagia assessed by the combination of EAT-10 and FEES. These findings need to be prospectively tested in a larger cohort of IIM patients.

Anti-synthetase syndrome: a rare and challenging diagnosis for bilateral ground-glass opacities-a case report with literature review.

BACKGROUND: Anti-synthetase syndrome (ASS) is an uncommon immune-mediated entity characterized by myositis, interstitial lung disease (ILD), non-erosive arthritis, and less common features such as fever, Raynaud's phenomenon, and skin changes in association with anti-aminoacyl-transfer-RNA antibodies, most commonly anti-Jo-1 antibodies. CASE PRESENTATION: We present a challenging and rare case of ASS-associated ILD presenting with unexplained respiratory symptoms and bilateral infiltrates on chest imaging during the COVID-19 pandemic. High clinical suspicion for ASS with early appropriate therapy with corticosteroids and immunosuppressive agents led to marked clinical improvement. CONCLUSION: High index of suspicion for ASS is mandated in patients with unexplained ILD. A comprehensive autoimmune work-up is important as an early treatment with corticosteroids with or without immunomodulators improves patient outcomes and survival in an otherwise poor prognostic disease.

Clinical features of anti-synthetase syndrome associated interstitial lung disease: a retrospective cohort in China.

BACKGROUND: Anti-synthetase syndrome (ASSD) is a chronic autoimmune condition characterized by antibodies directed against an aminoacycl transfer RNA synthetase (ARS) along with a group of clinical features including the classical clinical triad: inflammatory myopathy, arthritis, and interstitial lung disease (ILD). ASSD is highly heterogenous due to different organ involvement, and ILD is the main cause of mortality and function loss, which presents as different patterns when diagnosed. We designed this retrospective cohort to describe the clinical features and disease behaviour of ASSD associated ILD. METHODS: Data of 108 cases of ASSD associated ILD were retrospectively collected in Beijing Chaoyang Hospital from December 2017 to March 2019. Data were obtained from the Electronic Medical Record system. Patients were divided into 5 groups according to distinct aminoacyl tRNA synthetase (ARS) antibodies. RESULTS: Overall, 108 consecutive patients were recruited. 33 were JO-1 positive, 30 were PL-7 positive, 23 were EJ positive, 13 were PL-12 positive and 9 were OJ positive. The JO-1 (+) group had a significant higher rate of mechanic's hand (57.6%) than other 4 groups. Polymyositis/dermatomyositis (PM/DM) was diagnosed in 25 (23.1%) patients and no difference was observed among the 5 groups. The PL-7 (+) group had a higher frequency of UIP pattern (13.3%) than the other 4 groups but the difference was not significant, and the EJ (+) group had the most frequent OP pattern (78.2%), which was significantly higher than the PL-7 (+) (P < 0.001) and PL-12 (+) groups (P = 0.025). The median follow-up time was 10.7 months, during which no patients died. All received prednisone treatment, with or without immunosuppressants. At the 6-month follow-up, 96.3% of all patients (104/108) had a positive response to therapy, the JO-1 (+) and EJ (+) groups had a significantly higher improvement of forced vital capacity than the other 3 groups (P < 0.05), and the PL-7 group had the lowest FVC improvement (P < 0.05). The JO-1 (+) group and EJ (+) group had significantly higher anti-Ro-52 positive occurrence than the other 3 groups (P < 0.05). CONCLUSION: Anti PL-7 antibody had the same frequency as anti-JO-1 in ASSD-ILD, in which the ILD pattern was different with distinct anti-ARS antibodies. Most ASSD-ILD had a positive response to steroid therapies, with or without immunosuppressants. The PL-7 (+) group had the highest occurrence of UIP pattern, and a significantly lower response to therapy.

[Clinical and immunological characteristics of patients with anti-synthetase syndrome complicated with cardiac involvement].

OBJECTIVE: To investigate the clinical and immunological features of cardiac involvement in patients with anti-synthetase syndrome (ASS). METHODS: In the study, 96 patients diagnosed with ASS hospitalized in the Department of Rheumatology and Immunology, Peking University People's Hospital from April 2003 to November 2020 were included. The patients were divided into two groups according to whether they were accompanied with cardiac involvement. Demographic features, clinical characteristics (Gottron's sign/papules, muscle damage, etc.), comorbidities, laboratory indices (creatine kinase, inflammatory indicators, immunoglobulin, complement, lymphocyte subset, autoantibodies, etc.) were collected and the differences between the two groups were analyzed statistically. RESULTS: The prevalence of cardiac involvement in the patients with ASS was 25.0% (24/96). The ASS patients complicated with cardiac involvement presented with elevated cardiac troponin I (cTnI, 75.0%, 18/24), pericardial effusion (33.3%, 8/24), reduction of left ventricular function (33.3%, 8/24) and valves regurgitation (33.3%, 8/24). The age of onset of the patients with cardiac involvement was older than that of the patients without cardiac involvement [(54.58±10.58) years vs. (48.47±13.22) years, P=0.043). Arthritis was observed less frequently in the patients with cardiac involvement than those without cardiac involvement (37.5% vs. 61.1%, P=0.044). In addition, rapidly progressive interstitial lung disease (54.2% vs. 30.6%, P=0.037) was observed more frequently in the patients with cardiac involvement than those without cardiac involvement. As compared with the ASS patients without cardiac involvement, C-reactive protein (CRP) [(13.55 (8.96, 38.35) mg/L vs. 4.60 (1.37, 17.40) mg/L, P=0.001], and lactate dehydrogenase (LDH) [408.0 (255.0, 587.0) U/L vs. 259.5 (189.8, 393.8) U/L, P=0.007] were significantly higher in the patients with cardiac involvement. Anti-Ro-52 antibody was detected more commonly in the ASS patients with cardiac involvement compared with the patients without cardiac involvement (91.7% vs. 69.4%, P=0.029). No significant differences were found in the comorbidities, alanine transaminase (ALT), aspartate transaminase (AST), creatine kinase (CK), erythrocyte sedimentation rate (ESR), ferritin (Fer), immunoglobulin G (IgG), complement 3 (C3), complement 4 (C4), lymphocyte subset between the two groups. CONCLUSION: Cardiac involvement is common in ASS, mainly manifested as myocardial damage. It is necessary to be aware of cardiac complications in patients with elevated CRP, elevated LDH and positive anti-Ro-52 antibody.